Liquid dispensing systems in the present state of the art suffer certain shortcomings, especially with those systems adapted to carefully deliver reagent to peptide synthesis apparatus. For instance, in a typical reagent dispenser arrangement, liquid is driven from a reservoir pneumatically (i.e., by application of pressurized gas thereto) sufficient to dispense a relatively small volume of reagent for downstream reaction. Such dispensing systems are typically called upon to deliver a precisely-metered quantity of liquid reagent; such as solvent buffers and the like to a peptide synthesizer apparatus, for instance as shown in U.S. Pat. No. 3,531,258 to Merrifield et al, or in U.S. Pat. No. 3,557,077 to Brunfeldt et al (herein incorporated by reference).
Now, as workers know, the application and termination of a pneumatic pulse (e.g., pressurized air, or gas inert to liquid) to effect such a dispensing is a rather inexact science and various, relatively cumbersome controls have been resorted-to to better control the dispensing of such liquid. For instance, pneumatic pump means may be controlled to deliver reagent to a receiving reactor, being terminated at the proper time, and to the extent possible, when a prescribed "dose" is delivered. However, such systems typically suffer from poor control and relatively troublesome inertia effects-- for instance, termination of applied pumping pressure is difficult to control precisely and will typically allow pumping to continue feeding liquid beyond the desired level ("over-shoot"). Of course various expedients have been resorted-to to handle this problem; for instance, venting of the pneumatic pumping system immediately upon cessation of driving pressure.
However, such venting, in itself, introduces certain problems. For instance, the vented gas can carry-off a certain portion of the liquid handled, especially where it is highly volatile, as is characteristic of many peptide synthesis reagents. By way of illustration, note the arrangement in U.S. Pat. No. 3,536,450 to Dus et al, where for chemical analytical purposes, a reagent is dispensed from a vessel (see vessel 41, FIG. 1) by applying pressurized gas to the liquid surface and thrust the liquid up a "riser" tube to its destination-- here venting could likely deplete the liquid volume and possibly change the proportions of its constituents. That is, such a dispenser arrangement is typically terminated by interruption of dispensing pressure with contemporaneous pressure relief (venting to atmosphere) to achieve a fast pneumatic response. Now, obviously, to the extent any of the liquid contents (in vessel 41) are volatile under the operating conditions, they will, to a greater or lesser extent, be carried-off with the vented drive-gas. Moreover, since the storage vessel used is typically rather capacious and adapted to hold large volumes of liquid, it will typically require the application of relatively massive doses of pressurized gas to expel liquid; and when this gas volume is vented a good deal will be lost to atmosphere with each dispensing cycle.
Moreover, in instances where the dispensed liquids have a relatively high vapor pressure at the ambient conditions (e.g., temperature), evaporative losses of reagent will be quite high. This will not only prove expensive, but where the reagent includes organic solvents, it may present safety and air pollution problems. Also, such vapor loss through venting can seriously upset processing performance (e.g., peptide synthesis reactions) by virtue of allowing reagent concentration to shift, due to preferential vaporization of the more volatile constituents. This can become quite serious over a prolonged operating period of the system (e.g., through a series of many reagent-dispensing cycles). This is a special problem with certain reagent dispensers used in peptide synthesizers where, for instance, an unacceptable shift in the concentration of a critical semi-volatile reagent like anhydrous hydrochloric acid can occur (the acid being either dissolved in glacial acetic acid or in dioxane) due to acid evaporation during venting. Clearly such a loss becomes progressively more serious as the reagent volume in the storage vessel decreases, and after repeated venting cycles.
The present invention is adapted to provide a solution to such problems by use of a small intermediate vessel, or "vestibule chamber", at the outlet of a storage container, this chamber being independently pressure-evacuated and vented; and, preferably, automatically replenished.
More particularly, such problems are avoided with the invention by using such an intermediate vessel between a liquid-storage reservoir and the associated "use-station" in a system. For instance, the arrangement of the Dus patent above, can be so modified by interposition of such a vestibule chamber between reservoir 41 and receiving manifold 27. Thus, the pneumatic system driving liquid from a storage reservoir need not be vented at all, and need be operative only sufficient to maintain this vestibule chamber satisfactorily full, serving no delivery or metering function and requiring no pneumatic pumping for each small liquid volume dispensed. Similarly, since the volume of this intermediate chamber is relatively small, the mass of pumping gas needed for each liquid dose therefrom is likewise considerably reduced-- as is the volume of gas vented with each dose and the overall dispensing-vessel air space and contained liquid volume (thus minimizing vent-evaporation).
Such arrangement according to the invention, will of course, also reduce the consumption of dispensing gas needed since much less will need be vented; also it can improve the response speed of the delivery system and its efficiency since the volumes of liquid and gas involved are so radically reduced, reducing the associated inertia and delay. Also, it will become relatively easier to assure that a prescribed volume of reagent is delivered more precisely as well as more quickly and simply, as will be recognized by workers in the art upon consideration of the following description.
Thus, it is an object of the present invention to provide improved techniques and associated apparatus for solving the foregoing problems and providing the foregoing features of advantage. A related object is to provide a reagent dispensing arrangement including an intermediate "vestibule chamber". Yet another object is to provide such an arrangement and such a chamber in conjunction with pneumatic reagent delivery means. Yet a further object is to provide a pneumatic reagent dispensing apparatus wherein the loss of vented gas and the associated loss of volatile reagent is reduced.
A related object is to reduce reagent evaporation with venting, as well as related shifts in reagent concentration. Still another object is to reduce reagent evaporation and solvent losses in peptide synthesis apparatus, as well as to minimize, if not eliminate, resulting air pollution and safety problems. Yet another object is to provide a reagent dispensing system for peptide synthesis apparatus exhibiting improved overall precision in metering and efficiency in delivery of reagent.
These and other objects of the invention will become more apparent from the following description and appended claims, reference being made to the accompanying drawings forming a part of the specification wherein like referenced characters denote corresponding parts in the several views.